S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt
S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt
复制标题
S6K 抑制通过 Akt 的 PDK1 磷酸化提供心脏保护，防止心肌梗塞。
DOI：
10.1042/bj20110033
复制
发表时间：
2012-01-01
影响因子：
4.1
通讯作者：
Yang, Zhongzhou
中科院分区：
文献类型：
--
作者：
Di, Ruomin;Wu, Xiangqi;Yang, Zhongzhou
在本研究中，我们观察到小鼠心肌梗死（MI）引起的核糖体蛋白S6K （S6激酶）的快速和强烈激活。由于S6K的激活促进细胞生长，我们假设S6K活性的增加有助于心肌梗死后的病理性心脏重构，而抑制S6K激活可能会防止心脏异常重构并改善心功能。在小鼠实验中，雷帕霉素有效抑制心脏S6K的激活，显著改善心肌梗死后的心功能。雷帕霉素处理小鼠的心脏重量/体重比和纤维化面积显著减少。在雷帕霉素处理的小鼠中，与小鼠对照组相比，心肌细胞重构和细胞凋亡减少。同样，PP-4708671对S6K的抑制作用与雷帕霉素对心肌梗死的保护作用相似。在机制上，我们观察到在雷帕霉素和pf -4708671处理的心脏中，Thr（308）磷酸化和Akt活化显著增强。在给药雷帕霉素的情况下，心肌细胞特异性缺失PDK1（磷酸肌球蛋白依赖性激酶1）和Akt1/3可消除心肌梗死后的心脏保护作用。这些结果表明，抑制S6K通过增强Akt信号传导，对小鼠心肌梗死后左心室功能产生有益影响，并减轻心肌梗死后小鼠的不良重构，提示雷帕霉素和PP-4708671对心肌梗死后患者的治疗价值。
In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PP-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr(308) phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositicle-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PP-4708671 in treating patients following an MI.